Article

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Received:
Accepted:
Published online:

Abstract

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined 2,000 individuals for each of 7 major diseases and a shared set of 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 × 10-7: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn’s disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10-5 and 5 × 10-7) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

  • Subscribe to Nature for full access:

    $199

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    & Genome-wide association studies for common diseases and complex traits. Nature Rev. Genet. 6, 95–108 (2005)

  2. 2.

    & Evaluating coverage of genome-wide association studies. Nature Genet. 38, 659–662 (2006)

  3. 3.

    A haplotype map of the human genome. Nature 437, 1299–1320 (2005)

  4. 4.

    & Evidence-based health policy—lessons from the Global Burden of Disease Study. Science 274, 740–743 (1996)

  5. 5.

    Chi-square tests with one degree of freedom: Extension of the Mantel–Haenszel procedure. J. Am. Stat. Ass. 58, 690–700 (1963)

  6. 6.

    , & Problems of reporting genetic associations with complex outcomes. Lancet 361, 865–872 (2003)

  7. 7.

    et al. Genetic signatures of strong recent positive selection at the lactase gene. Am. J. Hum. Genet. 74, 1111–1120 (2004)

  8. 8.

    et al. Microsatellite variation and evolution of human lactase persistence. Hum. Genet. 117, 329–339 (2005)

  9. 9.

    et al. Positive natural selection in the human lineage. Science 312, 1614–1620 (2006)

  10. 10.

    et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. advance online publication, doi:10.1038/ng2068 (2007 June 6)

  11. 11.

    , & Inference of population structure using multilocus genotype data: linked loci and correlated allele frequencies. Genetics 164, 1567–1587 (2003)

  12. 12.

    , & Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000)

  13. 13.

    , & Synthetic maps of human gene frequencies in Europeans. Science 201, 786–792 (1978)

  14. 14.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nature Genet. 38, 904–909 (2006)

  15. 15.

    & Genomic control for association studies. Biometrics 55, 997–1004 (1999)

  16. 16.

    in Handbook of Statistical Genetics (eds Balding, D. J., Bishop, M. & Cannings, C.) 939–960 (Wiley, New York, 2003)

  17. 17.

    & Of flies and man: Drosophila as a model for human complex traits. Annu. Rev. Genomics Hum. Genet. 7, 339–367 (2006)

  18. 18.

    , , , & Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J. Natl. Cancer Inst. 96, 434–442 (2004)

  19. 19.

    et al. Replication of genome-wide association signals in U.K. samples reveals risk loci for type 2 diabetes. Science online publication, doi:10.1126/science.1142364 (2007 April 26)

  20. 20.

    et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nature Genet. advance online publication, doi:10.1038/ng2043 (2007 April 26)

  21. 21.

    et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science online publication, doi:10.1126/science.1142382 (2007 April 26)

  22. 22.

    Diabetes Genetics Institute. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science online publication, doi:10.1126/science.1142358 (2007 April 26)

  23. 23.

    et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nature Genet. advance online publication, doi:10.1038/ng2061 (2007 June 6)

  24. 24.

    et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007)

  25. 25.

    et al. Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science 305, 869–872 (2004)

  26. 26.

    , & Bipolar disorder. Lancet 359, 241–247 (2002)

  27. 27.

    , & The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J. Med. Genet. 42, 193–204 (2005)

  28. 28.

    et al. The heritability of bipolar affective disorder and the genetic relationship to unipolar depression. Arch. Gen. Psychiatry 60, 497–502 (2003)

  29. 29.

    et al. The familial transmission of bipolar illness. Arch. Gen. Psychiatry 44, 441–447 (1987)

  30. 30.

    et al. Combined analysis from eleven linkage studies of bipolar disorder provides strong evidence of susceptibility loci on chromosomes 6q and 8q. Am. J. Hum. Genet. 77, 582–595 (2005)

  31. 31.

    & The beginning of the end for the Kraepelinian dichotomy. Br. J. Psychiatry 186, 364–366 (2005)

  32. 32.

    et al. Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth. Proc. Natl Acad. Sci. USA 100, 289–294 (2003)

  33. 33.

    et al. Schizophrenia and affective disorders—cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am. J. Hum. Genet. 69, 428–433 (2001)

  34. 34.

    & Neurological channelopathies. Postgrad. Med. J. 81, 20–32 (2005)

  35. 35.

    et al. Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments. Mol. Psychiatry 7 (Suppl. 1). S71–S80 (2002)

  36. 36.

    et al. Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. Mol. Psychiatry 7, 571–578 (2002)

  37. 37.

    & Pathophysiology of coronary artery disease. Circulation 111, 3481–3488 (2005)

  38. 38.

    et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364, 937–952 (2004)

  39. 39.

    , & Genetics of atherosclerosis. Annu. Rev. Genomics Hum. Genet. 5, 189–218 (2004)

  40. 40.

    & Genetic susceptibility to coronary artery disease: from promise to progress. Nature Rev. Genet. 7, 163–173 (2006)

  41. 41.

    et al. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. Nature Genet. 36, 233–239 (2004)

  42. 42.

    et al. A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction. Nature Genet. 38, 68–74 (2006)

  43. 43.

    , , & Genetic susceptibility to myocardial infarction and coronary artery disease. Hum. Mol. Genet. 15 (Spec. No. 2). R117–R123 (2006)

  44. 44.

    & Tumor suppression by Ink4a–Arf: progress and puzzles. Curr. Opin. Genet. Dev. 13, 77–83 (2003)

  45. 45.

    & p15INK4B is a potential effector of TGF-β-induced cell cycle arrest. Nature 371, 257–261 (1994)

  46. 46.

    et al. Smad expression in human atherosclerotic lesions: evidence for impaired TGF-β/Smad signaling in smooth muscle cells of fibrofatty lesions. Arterioscler. Thromb. Vasc. Biol. 24, 1391–1396 (2004)

  47. 47.

    et al. A methylthioadenosine phosphorylase (MTAP) fusion transcript identifies a new gene on chromosome 9p21 that is frequently deleted in cancer. Oncogene 19, 5747–5754 (2000)

  48. 48.

    , , , & Human mitochondrial C1-tetrahydrofolate synthase: gene structure, tissue distribution of the mRNA, and immunolocalization in Chinese hamster ovary calls. J. Biol. Chem. 278, 43178–43187 (2003)

  49. 49.

    & Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase. Arch. Biochem. Biophys. 442, 196–205 (2005)

  50. 50.

    et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genet. 10, 111–113 (1995)

  51. 51.

    et al. MTHFR 677C→T polymorphism and risk of coronary heart disease: a meta-analysis. J. Am. Med. Assoc. 288, 2023–2031 (2002)

  52. 52.

    et al. Primed, constant infusion with [2H3]serine allows in vivo kinetic measurement of serine turnover, homocysteine remethylation, and transsulfuration processes in human one-carbon metabolism. Am. J. Clin. Nutr. 72, 1535–1541 (2000)

  53. 53.

    et al. Three siblings with nonketotic hyperglycinaemia, mildly elevated plasma homocysteine concentrations and moderate methylmalonic aciduria. J. Inherit. Metab. Dis. 23, 520–522 (2000)

  54. 54.

    The ADAMTS proteases, extracellular matrix, and vascular disease — Waking the sleeping giant(s)!. Arterioscler. Thromb. Vasc. Biol. 25, 12–14 (2005)

  55. 55.

    et al. The role of ADAMTS-1 in atherosclerosis: Remodeling of carotid artery, immunohistochemistry, and proteolysis of versican. Arter. Thromb. Vas. Bio. 25, 180–185 (2004)

  56. 56.

    et al. European evidence based consensus on the diagnosis and management of Crohn's disease: current management. Gut 55 (Suppl. 1). i16–i35 (2006)

  57. 57.

    Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nature Clin. Pract. Gastroenterol. Hepatol. 3, 390–407 (2006)

  58. 58.

    , , & Ulcerative-colitis and Crohns-disease in an unselected population of monozygotic and dizygotic twins — a study of heritability and the influence of smoking. Gut 29, 990–996 (1988)

  59. 59.

    , , & New genes in inflammatory bowel disease: lessons for complex diseases? Lancet 367, 1271–1284 (2006)

  60. 60.

    et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001)

  61. 61.

    et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001)

  62. 62.

    et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nature Genet. 29, 223–228 (2001)

  63. 63.

    et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006)

  64. 64.

    et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39, 207–211 (2007)

  65. 65.

    et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007)

  66. 66.

    et al. Novel crohn disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007)

  67. 67.

    , , & Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006)

  68. 68.

    Biological aspects of macrophage-stimulating protein (MSP) and its receptor. Ciba Found Symp. 212 183–191 discussion 192–197 (1997)

  69. 69.

    , , , & NKX2.3 is required for MAdCAM-1 expression and homing of lymphocytes in spleen and mucosa-associated lymphoid tissue. EMBO J. 19, 2015–2023 (2000)

  70. 70.

    et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Hum. Mol. Genet. 14, 3499–3506 (2005)

  71. 71.

    et al. Human native soluble CD40L is a biologically active trimer, processed inside microsomes. J. Biol. Chem. 271, 5965–5967 (1996)

  72. 72.

    , & Hypertension; Principles and Practice (Taylor Francis Group, 2005)

  73. 73.

    & The Genetics of Diabetes Mellitus (Academic Press, London, 1982)

  74. 74.

    et al. Genetics of hypertension: Lessons learnt from Mendelian and polygenic syndromes. Clin. Exp. Hypertens. 26, 611–620 (2004)

  75. 75.

    , , & Genetics of essential hypertension. Hum. Mol. Genet. 13, R169–R175 (2004)

  76. 76.

    et al. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nature Genet. 37, 243–253 (2005)

  77. 77.

    et al. Genome-wide mapping of human loci for essential hypertension. Lancet 361, 2118–2123 (2003)

  78. 78.

    et al. Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study. Hum. Mol. Genet. 14, 1805–1814 (2005)

  79. 79.

    et al. Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population. Circulation 112, 3423–3429 (2005)

  80. 80.

    et al. Molecular cloning of cDNA encoding the Ca2+ release channel (ryanodine receptor) of rabbit cardiac muscle sarcoplasmic reticulum. J. Biol. Chem. 265, 13472–13483 (1990)

  81. 81.

    , & Ryanodine receptor channelopathies. Biochem. Biophys. Res. Commun. 322, 1280–1285 (2004)

  82. 82.

    , & The epidemiology of rheumatoid arthritis and the use of linkage and association studies to identify disease genes (Birkhauser, Basel, 2005)

  83. 83.

    & Polygenic susceptibility in rheumatoid arthritis. Ann. Rheum. Dis. 50, 343–346 (1991)

  84. 84.

    , & The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987)

  85. 85.

    et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am. J. Hum. Genet. 68, 927–936 (2001)

  86. 86.

    et al. Whole-genome scan, in a complex disease, using 11,245 single-nucleotide polymorphisms: comparison with microsatellites. Am. J. Hum. Genet. 75, 54–64 (2004)

  87. 87.

    et al. Whole-genome linkage analysis of rheumatoid arthritis susceptibility loci in 252 affected sibling pairs in the United Kingdom. Arthritis Rheum. 46, 632–639 (2002)

  88. 88.

    et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004)

  89. 89.

    , , , & Investigation of genetic variation across PTPN22 in UK rheumatoid arthritis (RA) patients. Ann. Rheum. Dis. 66, 683–686 (2006)

  90. 90.

    , , & Human immune disorder arising from mutation of the α chain of the interleukin-2 receptor. Proc. Natl Acad. Sci. USA 94, 3168–3171 (1997)

  91. 91.

    et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773–779 (2005)

  92. 92.

    , & Type 1 diabetes: recent developments. Br. Med. J. 328, 750–754 (2004)

  93. 93.

    , , , & Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs: a nationwide follow-up study. Diabetes 52, 1052–1055 (2003)

  94. 94.

    et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genet. 38, 617–619 (2006)

  95. 95.

    Statistical false positive or true disease pathway? Nature Genet. 38, 731–733 (2006)

  96. 96.

    , & Protein tyrosine phosphatases and the immune response. Nature Rev. Immunol. 5, 43–57 (2005)

  97. 97.

    et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nature Genet. 36, 337–338 (2004)

  98. 98.

    Association of the interleukin-2 receptor alpha (IL-2Rα)/CD25 gene region with Graves’ disease using a multilocus test and tag SNPs. Clin. Endocrinol. 66, 508–512 (2007)

  99. 99.

    et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nature Genet. 39, 329–337 (2007)

  100. 100.

    , & Global and societal implications of the diabetes epidemic. Nature 414, 782–787 (2001)

  101. 101.

    , & Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333–1346 (2005)

  102. 102.

    et al. The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genet. 26, 76–80 (2000)

  103. 103.

    et al. Large-scale association studies of variants in genes encoding the pancreatic β-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52, 568–572 (2003)

  104. 104.

    et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nature Genet. 38, 320–323 (2006)

  105. 105.

    & TCF7L2: the biggest story in diabetes genetics since HLA? Diabetologia 50, 1–4 (2007)

  106. 106.

    et al. Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nature Genet. 39, 218–225 (2007)

  107. 107.

    et al. Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 55, 2890–2895 (2006)

  108. 108.

    , & Inhibition of cyclin-dependent kinase 5 activity protects pancreatic β cells from glucotoxicity. J. Biol. Chem. 281, 28858–28864 (2006)

  109. 109.

    et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007)

  110. 110.

    , & Genome-wide strategies for detecting multiple loci that influence complex diseases. Nature Genet. 37, 413–417 (2005)

  111. 111.

    et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nature Genet. 37, 1243–1246 (2005)

  112. 112.

    & The complex interplay among factors that influence allelic association. Nature Rev. Genet. 5, 89–100 (2004)

  113. 113.

    , , & Population stratification in the candidate gene study: fatal threat or red herring? Psychol. Bull. 130, 66–79 (2004)

  114. 114.

    , , , & Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nature Genet. 33, 177–182 (2003)

  115. 115.

    & The distribution of the effects of genes affecting quantitative traits in livestock. Genet. Sel. Evol. 33, 209–229 (2001)

  116. 116.

    et al. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature Genet. 38, 879–887 (2006)

  117. 117.

    , , , & How many genes underlie the occurrence of common complex diseases in the population? Int. J. Epidemiol. 34, 1129–1137 (2005)

  118. 118.

    et al. Predictive testing for complex diseases using multiple genes: fact or fiction? Genet. Med. 8, 395–400 (2006)

  119. 119.

    , & Research diagnostic criteria: rationale and reliability. Arch. Gen. Psychiatry 35, 773–782 (1978)

  120. 120.

    et al. SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Arch. Gen. Psychiatry 47, 589–593 (1990)

  121. 121.

    et al. Concurrent validity of the OPCRIT diagnostic system. Comparison of OPCRIT diagnoses with consensus best-estimate lifetime diagnoses. Br. J. Psychiatry 169, 58–63 (1996)

  122. 122.

    , & A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. Arch. Gen. Psychiatry 48, 764–770 (1991)

  123. 123.

    et al. Operation of the schizophrenia susceptibility gene, neuregulin 1, across traditional diagnostic boundaries to increase risk for bipolar disorder. Arch. Gen. Psychiatry 62, 642–648 (2005)

  124. 124.

    et al. Genetic variation of brain-derived neurotrophic factor (BDNF) in bipolar disorder: case-control study of over 3000 individuals from the UK. Br. J. Psychiatry 188, 21–25 (2006)

  125. 125.

    et al. A genomewide linkage study of 1,933 families affected by premature coronary artery disease: The British Heart Foundation (BHF) Family Heart Study. Am. J. Hum. Genet. 77, 1011–1020 (2005)

  126. 126.

    Classification of inflammatory bowel disease. Scand. J. Gastroenterol. (Suppl.) 170, 2–6; discussion. 6–9 (1989)

  127. 127.

    et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988)

  128. 128.

    , & A comparison of the performance of different methods of disease classification for rheumatoid arthritis. Results of an analysis from a nationwide twin study. J. Rheumatol. 21, 1420–1426 (1994)

  129. 129.

    et al. The Arthritis and Rheumatism Council's National Repository of Family Material: pedigrees from the first 100 rheumatoid arthritis families containing affected sibling pairs. Br. J. Rheumatol. 33, 970–976 (1994)

  130. 130.

    , , , & The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. Br. J. Rheumatol. 33, 735–739 (1994)

  131. 131.

    et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53, 3020–3023 (2004)

  132. 132.

    et al. A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am. J. Hum. Genet. 69, 553–569 (2001)

  133. 133.

    et al. Parent–offspring trios: a resource to facilitate the identification of type 2 diabetes genes. Diabetes 48, 2475–2479 (1999)

  134. 134.

    et al. Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes 55, 2640–2644 (2006)

  135. 135.

    & Cohort profile: 1958 British birth cohort (National Child Development Study). Int. J. Epidemiol. 35, 34–41 (2006)

  136. 136.

    et al. Lifecourse influences on health among British adults: Effects of region of residence in childhood and adulthood. Int. J. Epidemiol. Advance online publication, doi:10.1093/ije/dyl309 (2007 January 25)

  137. 137.

    et al. Genotyping over 100,000 SNPs on a pair of oligonucleotide arrays. 1, 104–105. Nat Methods 1, 104–105 (2004)

  138. 138.

    et al. Dynamic model based algorithms for screening and genotyping over 100 K SNPs on oligonucleotide microarrays. Bioinformatics 21, 1958–1963 (2005)

  139. 139.

    & A genotype calling algorithm for affymetrix SNP arrays. Bioinformatics 22, 7–12 (2006)

  140. 140.

    Affymetrix. in Technical Report. (2006)

  141. 141.

    Enhancements to Aid Interpretation of Probability Plots. Statistician 31, 211–220 (1982)

  142. 142.

    & Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 165, 2213–2233 (2003)

  143. 143.

    , , , & A new multipoint method for genome-wide association studies via imputation of genotypes. Nature Genet. doi:10.1038/ng2088 (in the press)

Download references

Acknowledgements

The principal funder of this project was the Wellcome Trust. Case collections were funded by: Arthritis Research Campaign, BDA Research, British Heart Foundation, British Hypertension Society, Diabetes UK, Glaxo-Smith Kline Research and Development, Juvenile Diabetes Research Foundation, National Association for Colitis and Crohn’s disease, SHERT (The Scottish Hospitals Endowment Research Trust), St Bartholomew’s and The Royal London Charitable Foundation, UK Medical Research Council, UK NHS R&D and the Wellcome Trust. Statistical analyses were funded by a Commonwealth Scholarship, EU, EPSRC, Fundação para a Ciência e a Tecnologia (Portugal), National Institutes of Health, National Science Foundation and the Wellcome Trust. We acknowledge the many physicians, research fellows and research nurses who contributed to the various case collections, and the collection teams and senior management of the UK Blood Services responsible for the UK Blood Services Collection. For the 1958 Birth Cohort, venous blood collection was funded by the UK Medical Research Council and cell-line production, DNA extraction and processing by the Juvenile Diabetes Research Foundation and the Wellcome Trust. We recognize the contributions of: P. Shepherd (1958 Birth Cohort); those at Affymetrix responsible for genotype assay optimization, data production and data delivery (particularly S. Cawley, R. Mei, H. Fakhrai-Rad, H. Francis-Land, R. Pillai); L. Forty, G. Fraser, J. Heron, S. Hyde, A. Massey; F. Oyebode, E. Russell, M. Sinclair, A. Stern, N. Walker and S. Zammitt (recruitment and phenotypic assessment of BD cases); M. Yuille, B. Ollier and the UK DNA Banking Network and members of the BHF Family Heart Study Research Group (CAD case recruitment and DNA provision); S. Goldthorpe, D. Soars and J. Whittaker for CD collections; J. Pembroke, M. Bruce, S. Colville-Stewart, K. Edwards, L. Gatherer, C. Gemmell, K. Gilmour, S. Hampson, S. Hood, J. Hunt, J. Hussein, J. Jamieson, J. Kent, D. Lloyd, K. MacFarlane, S. Mellow, A. Nixon, J. Pheby, D. Picton, F. Porteus, P. Whitworth, K. Witte, A. Zawadzka, C. Mein and the Barts and The London Genome Centre (HT sample collection); H. Withers, the research nurses and the membership of the British Society for Paediatric Endocrinology and Diabetes (T1D case recruitment); and M. Sampson, S. O’Rahilly, S. Howell, M. Murphy and A. Wilson (T2D case recruitment). Essential informatics support was provided by the administration, systems, bioinformatics, data services and DNA teams of the JDRF/WT DIL; the Web System teams at the Sanger Institute (particularly R. Pettitt); D. Holland and R. Vincent. T. Dibling, C. Hind, D. Simpkin, P. Ewels and D. Moore provided genotyping assistance. Personal support was provided by: Arthritis Research Campaign (A.B., H.Do., S.E., P.G., S.H., A.H., S.J., C.P., A.S., D.S., W.T., J.Wo.); British Heart Foundation (S.G.B., N.J.S., A.Do., C.W.); Cancer Research UK (D.Ea.); Diabetes UK (R.M.F.); Cure Crohn’s and Colitis Fund (F.R.C.); CORE (C.M.O.); SIM (G.B.); Leverhulme Trust (A.P.M.); Throne-Holst Foundation (C.M.L.); UK Medical Research Council (D.P.K., M.D.T., J.R.P.); Vandervell Foundation (M.N.W.); and Wellcome Trust (D.G.C., L.R.C., C.M., J.Sat., M.T., A.T.H., E.Z., C.B., S.J.B., A.C., K.D., J.Gh., R.G., S.E.H., A.K., E.K., R.McG., S.P., R.R., P.Wh., D.W., P.De.).

Affymetrix GeneChip Mapping 500K Set Arrays 250K_Nsp_SNP and 250K_Sty2_SNP are deposited in NCBI GEO under accession numbers GPL3718 and GPL3720, respectively.

Author information

Author notes

    • The Wellcome Trust Case Control Consortium
    •  & David Bentley

    †Present address: Illumina Cambridge, Chesterford Research Park, Little Chesterford, Nr Saffron Walden, Essex CB10 1XL, UK.

Affiliations

  1. Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Adrian Building, University Road, Leicester LE1 7RH, UK.

    • Paul R. Burton
    • , Martin D. Tobin
    • , John R. Thompson
    •  & Martin D. Tobin (Leicester)
  2. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.

    • David G. Clayton
    • , John A. Todd
    • , Hin-Tak Leung
    • , David G. Clayton (Co-Chair)
    • , Sarah Nutland
    • , Helen E. Stevens
    • , Neil M. Walker
    • , David G. Clayton (Cambridge)
    • , David B. Dunger
    • , Barry Widmer
    • , Kate Downes
    •  & John A. Todd (Cambridge)
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.

    • Lon R. Cardon
    • , Dominic P. Kwiatkowski
    • , Mark I. McCarthy
    • , Jeffrey C. Barrett
    • , David Evans
    • , Andrew P. Morris
    • , Lon R. Cardon (Co-Chair)
    • , Kate S. Elliott
    • , Cecilia M. Lindgren
    • , Nigel W. Rayner
    • , Nicholas J. Timpson
    • , Eleftheria Zeggini
    • , Mark I. McCarthy (Oxford)
    • , Emily Lyons
    • , Fredrik Vannberg
    • , Adrian V. S. Hill (Oxford)
    • , Kirk A. Rockett
    • , Dominic P. Kwiatkowski (Oxford)
    • , Lon R. Cardon (Oxford)
    • , Yik Ying Teo
    •  & Adrian V. S. Hill
  4. Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.

    • Nick Craddock
  5. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Panos Deloukas
    • , Dominic P. Kwiatkowski
    • , Antony P. Attwood
    • , Dominic P. Kwiatkowski (Oxford)
    • , Suzannah J. Bumpstead
    • , Amy Chaney
    • , Kate Downes
    • , Mohammed J. R. Ghori
    • , Rhian Gwilliam
    • , Sarah E. Hunt
    • , Michael Inouye
    • , Andrew Keniry
    • , Emma King
    • , Ralph McGinnis
    • , Simon Potter
    • , Rathi Ravindrarajah
    • , Pamela Whittaker
    • , Claire Widden
    • , David Withers
    •  & David Bentley
  6. The Wellcome Trust, Gibbs Building, 215 Euston Road, London NW1 2BE, UK.

    • Audrey Duncanson
    •  & Panos Deloukas (Wellcome Trust Sanger Institute Hinxton)
  7. Oxford Centre for Diabetes, Endocrinology and Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Mark I. McCarthy
    • , Kate S. Elliott
    • , Christopher J. Groves
    • , Cecilia M. Lindgren
    • , Nigel W. Rayner
    • , Eleftheria Zeggini
    •  & Mark I. McCarthy (Oxford)
  8. Department of Haematology, University of Cambridge, Long Road, Cambridge CB2 2PT, UK.

    • Willem H. Ouwehand
    • , Antony P. Attwood
    • , James P. Boorman
    • , Barbara Cant
    • , Jennifer D. Jolley
    • , Alexandra S. Knight
    • , Kerstin Koch
    • , Niall C. Taylor
    • , Nicholas A. Watkins
    •  & Thilo Winzer
  9. National Health Service Blood and Transplant, Cambridge Centre, Long Road, Cambridge CB2 2PT, UK.

    • Willem H. Ouwehand
    • , James P. Boorman
    •  & Nicholas A. Watkins
  10. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.

    • Nilesh J. Samani
    • , Peter S. Braund
    • , Richard J. Dixon
    • , Massimo Mangino
    • , Suzanne Stevens
    •  & Nilesh J. Samani (Leicester)
  11. Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.

    • Peter Donnelly (Chair)
    • , Dan Davison
    • , Peter Donnelly
    • , Jonathan L. Marchini
    • , Chris C. A. Spencer
    • , Niall J. Cardin
    • , Teresa Ferreira
    • , Joanne Pereira-Gale
    • , Ingileif B. Hallgrimsdóttir
    • , Bryan N. Howie
    • , Zhan Su
    • , Yik Ying Teo
    • , Damjan Vukcevic
    •  & Peter Donnelly (Oxford)
  12. Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, UK.

    • Doug Easton
  13. National Health Service Blood and Transplant, Sheffield Centre, Longley Lane, Sheffield S5 7JN, UK.

    • Ursula Everson
  14. National Health Service Blood and Transplant, Brentwood Centre, Crescent Drive, Brentwood CM15 8DP, UK.

    • Judith M. Hussey
  15. The Welsh Blood Service, Ely Valley Road, Talbot Green, Pontyclun CF72 9WB, UK.

    • Elizabeth Meech
  16. The Scottish National Blood Transfusion Service, Ellen’s Glen Road, Edinburgh EH17 7QT, UK.

    • Christopher V. Prowse
  17. National Health Service Blood and Transplant, Southampton Centre, Coxford Road, Southampton SO16 5AF, UK.

    • Graham R. Walters
  18. Avon Longitudinal Study of Parents and Children, University of Bristol, 24 Tyndall Avenue, Bristol BS8 1TQ, UK.

    • Richard W. Jones
    • , Wendy L. McArdle
    • , Susan M. Ring
    •  & Marcus Pembrey
  19. Division of Community Health Services, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK.

    • David P. Strachan
  20. Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.

    • Marcus Pembrey
  21. University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK.

    • Gerome Breen
    •  & David St Clair (Aberdeen)
  22. Department of Psychiatry, Division of Neuroscience, Birmingham University, Birmingham B15 2QZ, UK.

    • Sian Caesar
    • , Katherine Gordon-Smith
    •  & Lisa Jones (Birmingham)
  23. Department of Psychological Medicine, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.

    • Katherine Gordon-Smith
    • , Christine Fraser
    • , Elaine K. Green
    • , Detelina Grozeva
    • , Marian L. Hamshere
    • , Peter A. Holmans
    • , Ian R. Jones
    • , George Kirov
    • , Valentina Moskvina
    • , Ivan Nikolov
    • , Michael C. O'Donovan
    • , Michael J. Owen
    • , Nick Craddock (Cardiff)
    •  & Nick Craddock
  24. SGDP, The Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK.

    • David A. Collier
    • , Amanda Elkin
    • , Anne Farmer
    • , Richard Williamson
    •  & Peter McGuffin (London)
  25. School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, NE1 4LP, UK.

    • Allan H. Young
    •  & I. Nicol Ferrier (Newcastle)
  26. LIGHT and LIMM Research Institutes, Faculty of Medicine and Health, University of Leeds, Leeds LS1 3EX, UK.

    • Stephen G. Ball
    • , Anthony J. Balmforth
    • , Jennifer H. Barrett
    • , D. Timothy Bishop
    • , Mark M. Iles
    • , Azhar Maqbool
    • , Nadira Yuldasheva
    • , Alistair S. Hall (Leeds)
    •  & Alistair S. Hall
  27. IBD Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 2QQ, UK.

    • Francesca Bredin
    • , Mark Tremelling
    • , Miles Parkes (Cambridge)
    •  & Miles Parkes
  28. Gastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.

    • Hazel Drummond
    • , Charles W. Lees
    • , Elaine R. Nimmo
    •  & Jack Satsangi (Edinburgh)
  29. Department of Medical & Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK.

    • Sheila A. Fisher
    • , Cathryn M. Lewis
    • , Clive M. Onnie
    • , Natalie J. Prescott
    • , Christopher G. Mathew (London)
    •  & Christopher G. Mathew
  30. Institute for Digestive Diseases, University College London Hospitals Trust, London, NW1 2BU, UK.

    • Alastair Forbes
  31. Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London SE1 7EH, UK.

    • Jeremy Sanderson
  32. Department of Gastroenterology & Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.

    • Jamie Barbour
    • , M. Khalid Mohiuddin
    • , Catherine E. Todhunter (Newcastle)
    •  & John C. Mansfield
  33. Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford OX2 6HE, UK.

    • Tariq Ahmad
    • , Fraser R. Cummings
    •  & Derek P. Jewell (Oxford)
  34. Medicine and Therapeutics, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, Grampian AB9 2ZB, UK.

    • John Webster (Aberdeen)
  35. Clinical Pharmacology Unit and the Diabetes and Inflammation Laboratory, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK.

    • Morris J. Brown
  36. Centre National de Genotypage, 2, Rue Gaston Cremieux, Evry, Paris 91057, France.

    • G. Mark Lathrop (Evry)
  37. BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK.

    • John Connell
    •  & Anna Dominiczak (Glasgow)
  38. Clinical Pharmacology and Barts and The London Genome Centre, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine, Charterhouse Square, London EC1M 6BQ, UK.

    • Carolina A. Braga Marcano
    • , Beverley Burke
    • , Richard Dobson
    • , Johannie Gungadoo
    • , Kate L. Lee
    • , Patricia B. Munroe
    • , Stephen J. Newhouse
    • , Abiodun Onipinla
    • , Chris Wallace
    • , Mingzhan Xue
    • , Mark Caulfield (London)
    •  & Mark Caulfield
  39. Cardiovascular Medicine, University of Oxford, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK.

    • Martin Farrall (Oxford)
    •  & Martin Farrall
  40. arc Epidemiology Research Unit, University of Manchester, Stopford Building, Oxford Rd, Manchester M13 9PT, UK.

    • Anne Barton
    • , Ian N. Bruce
    • , Hannah Donovan
    • , Steve Eyre
    • , Paul D. Gilbert
    • , Samantha L. Hider
    • , Anne M. Hinks
    • , Sally L. John
    • , Catherine Potter
    • , Alan J. Silman
    • , Deborah P. M. Symmons
    • , Wendy Thomson
    •  & Jane Worthington
  41. Department of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK.

    • David B. Dunger
    •  & Barry Widmer
  42. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter EX1 2LU, UK.

    • Timothy M. Frayling
    • , Rachel M. Freathy
    • , Hana Lango
    • , John R. B. Perry
    • , Michael N. Weedon
    • , Andrew T. Hattersley (Exeter)
    •  & Andrew T. Hattersley
  43. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DU, UK.

    • Timothy M. Frayling
    • , Rachel M. Freathy
    • , Hana Lango
    • , John R. B. Perry
    • , Beverley M. Shields
    • , Michael N. Weedon
    • , Andrew T. Hattersley (Exeter)
    •  & Andrew T. Hattersley
  44. Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London E1 1BB, UK.

    • Graham A. Hitman (London)
  45. Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK.

    • Mark Walker (Newcastle)
  46. The MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Rd, Bristol BS2 8PR, UK.

    • Nicholas J. Timpson
  47. MRC Laboratories, Fajara, The Gambia.

    • Melanie Newport
    • , Giorgio Sirugo (Gambia)
    • , David Conway
    •  & Muminatou Jallow
  48. Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Qld 4102, Australia.

    • Linda A. Bradbury
    • , Jennifer J. Pointon
    •  & Matthew A. Brown
  49. Botnar Research Centre, University of Oxford, Headington, Oxford OX3 7BN, UK.

    • Claire Farrar
    • , Paul Wordsworth
    •  & Matthew A. Brown
  50. Department of Medicine, Division of Medical Sciences, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

    • Jayne A. Franklyn
    • , Joanne M. Heward
    • , Matthew J. Simmonds
    •  & Stephen C. L. Gough
  51. Section of Cancer Genetics, Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK.

    • Sheila Seal
    • , Michael R. Stratton
    •  & Nazneen Rahman
  52. Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Michael R. Stratton
  53. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK.

    • Maria Ban
    • , An Goris
    • , Stephen J. Sawcer
    • , Alastair Compston
    •  & Alistair Compston
  54. *Lists of participants and affiliations appear at the end of the paper.

    • The Biologics in RA Genetics and Genomics (BRAGGS)
    •  & Breast Cancer Susceptibility Collaboration (UK)

Consortia

  1. The Wellcome Trust Case Control Consortium

    Management Committee

    Data and Analysis Committee

    UK Blood Services and University of Cambridge Controls

    1958 Birth Cohort Controls

    Bipolar Disorder

    Coronary Artery Disease

    Crohn’s Disease

    Hypertension

    Rheumatoid Arthritis

    Type 1 Diabetes

    Type 2 Diabetes

    Tuberculosis

    Ankylosing Spondylitis

    Autoimmune Thyroid Disease

    Breast Cancer

    Multiple Sclerosis

    Gambian Controls

    DNA, Genotyping, Data QC and Informatics

    Statistics

    Primary Investigators

Authors

    Competing interests

    Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

    Supplementary information

    PDF files

    1. 1.

      Supplementary Information

      This file contains Supplementary Notes on data quality control measures, interpretation of 'cluster' and 'signal' plots, calculation of Bayes factors and the CHIAMO genotype-calling algorithm; Supplementary Figures 1 – 25 with Legends and Supplementary Tables 1 - 16 with Legends.

    Comments

    By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.